The majority of breast cancers express estrogen receptor alpha (ER?) and are estrogen-dependent. In ER?- positive breast cancer, ER? antagonists decrease cell proliferation and tumor growth. Tamoxifen (Tam), an ER? antagonist in breast cancer cells, is the most widely used adjuvant therapy for patients diagnosed with ER?-positive breast cancer. While Tam treatment is effective for most patients, innate Tam resistance is observed in some patients and the development of Tam resistance after long-term treatment remains a clinically relevant outcome. The molecular mechanisms that underlie Tam resistance are not well understood. While Tam action is often attributed entirely to ER? antagonism, Tam sensitivity has been observed in breast cancer cells that lack ER? suggesting alternative mechanisms of Tam action. We have shown that GPER1 mediates Tam action in breast cancer cells via induction of IGFBP-1 expression and subsequent inhibition of IGF-1R-dependent cell signaling. Additionally, our data indicate that this GPER1-mediated mechanism of Tam action inhibits IGF-1-stimulated ER? phosphorylation. The role of IGFBPs during Tam treatment and the development of Tam resistance has not been adequately studied. GPER1-mediated mechanisms of Tam action in breast cancer cells modulate IGF-1R activity and inhibit phosphorylation-dependent ER? signaling. To test this hypothesis, three independent Aims are proposed. Included in all three Aims are experiments utilizing a panel of breast cancer cell lines to model Tam efficacy in multiple breast cancer subtypes. Completion of these aims will result in (1) Defining the role of IGFBP family members during Tam treatment, (2) Elucidating GPER1-mediated mechanisms that inhibit phosphorylation-dependent ER? activity in Tam- treated breast cancer cells, and (3) Determine the IGFBP-dependent molecular mechanisms that drive Tam resistance via modulation of growth factor signaling. Upon completion of these Aims, our knowledge regarding the molecular mechanisms of GPER1-mediated Tam action in breast cancer cells will be significantly increased and the molecular mechanisms of the role of GPER1 during the development of Tam resistance will be more clearly defined. Data obtained from these experiments will provide new models of understanding Tam action for future animal model and clinical studies of this commonly used therapeutic.